Project Abstract: Estrogen receptor alpha (ER?) is the primary therapeutic target in luminal breast cancer, which accounts for 70% of all cases. However, all of the approved endocrine therapies for breast cancer have been developed based on the assumption that ER? within cancer cells is their only/primary target. Given the importance of ER? and ER? ligands on immune function, this proposal aims to understand the mechanisms behind ER? action in the tumor microenvironment and how this biology can be targeted for therapeutic benefit. To this end, a novel mechanism by which ER? inhibits the activity of RIP140, a protein that serves as a NF-?B coactivator and a critical regulator of macrophage polarization will be explored. The central hypothesis of this work is that ER? affects the immune cell function in a manner that facilitates the growth and progression of tumors. Specifically, it is proposed that ER? activation disrupts the interaction between RIP140 and NF- ?B and in doing so reprograms macrophage function to create an immune environment within tumors conducive to growth and progression. In the first aim, the roles of ER?/RIP140 interactions in shaping the tumor microenvironment will be defined. In the second aim, the molecular mechanism(s) by which ER? regulates RIP140 to effect macrophage function will be explored. And finally, in the third aim, the therapeutic/translational implications of targeting the ER?/RIP140 axis will be elucidated. The outcomes of this work will advance the understanding of ER? biology and provide critical information upon which the efficacy of ER?- targeted therapies can be improved.